US2024226104A1PendingUtilityA1
Pi3k inhibitors, nanoformulations, and uses thereof
Est. expiryApr 20, 2041(~14.7 yrs left)· nominal 20-yr term from priority
A61K 31/337A61K 9/5169A61K 9/0019A61P 35/04A61K 31/519A61K 9/14A61K 45/06C07D 487/04
49
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Claims
Abstract
The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors, and compositions, nanoformulations and methods for treating diseases or disorders (e.g., breast cancer, pancreatic cancer, lung cancer, and lymphoma) with PBK inhibitors or composition thereof. Disclosed herein is a composition comprising: an effective amount of a PI3K inhibitor or a pharmaceutically acceptable salt thereof; and an albumin nanoparticle.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A composition comprising: an effective amount of a phosphatidylinositol 3-kinase (PI3K) inhibitor, or a pharmaceutically acceptable salt thereof; and an albumin nanoparticle.
2 . The composition of claim 1 , wherein the PI3K inhibitor is a Class I PI3K inhibitor.
3 . The composition of claim 2 , wherein the PI3K inhibitor is an isoform-selective PI3K inhibitor.
4 . The composition of claim 1 , wherein the PI3K inhibitor is a compound of formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
R 10 is selected from —C≡C—R x , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, and di-C 1 -C 4 -alkylamino;
R 11 is selected from C 1 -C 4 alkyl and hydrogen;
R 3 is an 8- to 10-membered bicyclic heteroaryl having 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from amino, C 1 -C 4 alkyl, and halo; and
R x is selected from a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S, aryl, hydrogen, and C 1 -C 4 alkyl, wherein the heteroaryl and aryl are optionally substituted with 1 or 2 substituents selected from C 1 -C 4 alkyl.
5 . The composition of claim 4 , wherein R 10 is —C≡C—R x , and R x is a 5-membered monocyclic heteroaryl having two nitrogen atoms, which is substituted with one C 1 -C 4 alkyl.
6 . The composition of claim 4 or claim 5 , wherein R 11 is methyl.
7 . The composition of any one of claims 4-6 , wherein R 12 is a pyrazolo[1,5-a]pyrimidine substituted with one amino group.
8 . The composition of any one of claims 4-7 , wherein the compound of formula (III) is:
9 . The composition of any of claims 1-8 , wherein the nanoparticle has a diameter between 50 and 200 nm.
10 . The composition of any of claims 1-9 , wherein the albumin nanoparticle encapsulates the PI3K inhibitor.
11 . The composition of any of claims 1-10 , wherein the albumin is human serum albumin or albumin from animal species.
12 . The composition of any of claims 1-11 , wherein the composition further comprises a chemotherapeutic agent.
13 . The composition of claim 12 , wherein the albumin nanoparticle encapsulates the chemotherapeutic agent.
14 . The composition of claim 12 or 13 , wherein the chemotherapeutic agent is paclitaxel.
15 . A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Q is CH or N;
A is aryl or a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and P;
R 1 is selected from hydrogen, halo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, —OR a1 , —N(R b1 )(R c1 ), —SO 2 R d1 , —SO 2 N(R e1 )(R f1 ), and —NHSO 2 R g1 , wherein R a1 , R b1 , R c1 , R d1 , R e1 , R f1 , and R g1 are each independently selected from hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl;
R 2 is selected from hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and a group of formula (II):
wherein:
D is a monocyclic heteroaryl or monocyclic heterocyclyl, each of which is optionally substituted with a C 1 -C 4 alkyl group;
X is a bond, —C(O)—, —NH—, or —C(O)NH—;
Y is —(CR a2 ) n -G 2 -, wherein each R a2 is independently selected from H and C 1 -C 4 alkyl, or wherein two R a2 together with the carbon atom(s) to which they are attached form a C 3 -C 7 cycloalkyl; G 2 is a bond, cycloalkylene, or heterocyclylene; and n is 0, 1, 2, or 3;
Z is —OR b2 , —SR c2 , —N(R d2 ) (R e2 ), or —CH 3 , wherein R b2 , R e2 , R d2 , and R e2 are each independently selected from hydrogen, aryl, arylalkyl, C 1 -C 4 alkyl, —C(O)—C 1 -C 40 alkyl, —C(O)—C 2 -C 40 alkenyl, and a group of formula (IIa):
and
R 3 is selected from hydrogen and a group -L 3 -E, wherein:
L 3 is a bond, C 1 -C 2 alkylene, —CH═CH—, —C≡C—, —C(O)—, —O—, —NH—, —S—, —C(O)O—, —C(O)NH—, —C(O)S—, arylene, cycloalkylene, heteroarylene, or heterocyclylene, or wherein L 3 comprises a combination of any two of such groups; and
E is a bicyclic heterocyclyl or bicyclic heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 1 -C 4 haloalkyl, oxo, —OR a3 , —N(R b3 )(R c3 ), —SO 2 R d3 , —SO 2 N(R e3 )(R f3 ), and —NHSO 2 R g3 , wherein R a3 , R b3 , R e3 , R d3 , R e3 , R f3 , and R g3 are each independently selected from hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl;
L is —(CR a4 R b4 ) m -G 4 -, wherein:
R a4 and R b4 are independently selected from hydrogen and C 1 -C 4 alkyl;
m is 0, 1, or 2; and
G 4 is a bond, —NHC(O)—, —NH—, —O—, or —S—; and
B is a bicyclic heteroaryl or bicyclic heterocyclyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, optionally substituted aryl, —OR a5 , —N(R b5 )(R c5 ), —SO 2 R d5 , —SO 2 N(R e5 )(R f5 ), and —NHSO 2 R g5 , wherein R a5 , R b5 , R c5 , R d5 , R e5 , R f5 , and R g5 are each independently selected from hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl;
wherein when R 3 is hydrogen, R 2 is a group of formula (II) and Z is not —CH 3 ; and
wherein when R 2 is hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkoxy, R 3 is a group -L 3 -E.
16 . The compound of claim 15 , wherein the compound is a compound of formula (Ia):
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein A is phenyl and R 1 is hydrogen.
18 . The compound of claim 15 , wherein the compound is a compound of formula (Ib):
or a pharmaceutically acceptable salt thereof.
19 . The compound of any one of claims 15-4 , or a pharmaceutically acceptable salt thereof, wherein D is a five-membered monocyclic heteroaryl or a 4- to 6-membered monocyclic heterocyclyl, each of which independently comprises 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and P.
20 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein D is selected from pyrrole, pyrazole, imidazole, imidazoline, oxazole, oxathiazole, oxadiazole, azetidine, pyrroline, pyrrolidine, and piperidine.
21 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein D has a structure selected from:
22 . The compound of any one of claims 15-7 , or a pharmaceutically acceptable salt thereof, wherein X is a bond or —C(O)—.
23 . The compound of any one of claims 15-8 , or a pharmaceutically acceptable salt thereof, wherein Y is —(CR a2 ) n —CH 2 —, wherein n is 0 or 1, and wherein each R a2 is hydrogen, or wherein the two R a2 groups, together with the carbon atom to which they are attached, form a cyclopropylene ring.
24 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the group —X—Y—Z has a formula selected from:
25 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Z is —OR b2 , wherein R b2 is selected from hydrogen, —C(O)—C 1 -C 40 alkyl, —C(O)—C 2 -C 40 alkenyl, and a group of formula (IIa).
26 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein Z is Z is —OR b2 , wherein R b2 is selected from hydrogen, —C(O)—C 15 -C 20 alkyl, —C(O)—C 15 -C 20 alkenyl, and a group of formula (IIa).
27 . The compound of claim 15 , wherein the compound is a compound of formula (Ic):
or a pharmaceutically acceptable salt thereof.
28 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from halo and a group of formula (II).
29 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 2 is halo.
30 . The compound of any one of claims 13-15 , or a pharmaceutically acceptable salt thereof, wherein L 3 is a bond, —CH 2 —CH 2 —, —CH═CH—, —C≡C—, —C(O)NH—, or a 5-membered heteroarylene having 1, 2, or 3 nitrogen atoms.
31 . The compound of any one of claims 13-16 , or a pharmaceutically acceptable salt thereof, wherein E has a formula:
wherein R′ and R″ are independently selected from C 1 -C 4 alkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 1 -C 4 haloalkyl, and —NHSO 2 R g3 , wherein R g3 is C 1 -C 4 alkyl.
32 . The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R′ is C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, and R″ is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and —NHSO 2 R g3 , wherein R g3 is C 1 -C 4 alkyl.
33 . The compound of claim 15 , wherein the compound is selected from:
and pharmaceutically acceptable salts thereof.
34 . A pharmaceutical composition comprising an effective amount of a compound of any one of claims 15-33 , or a pharmaceutically acceptable salt thereof.
35 . The pharmaceutical composition of claim 34 , wherein the composition further comprises an albumin nanoparticle.
36 . The pharmaceutical composition of claim 35 , wherein the nanoparticle has a diameter between 50 and 200 nm.
37 . The pharmaceutical composition of claim 35 or 36 , wherein the albumin nanoparticle encapsulates the compound.
38 . The pharmaceutical composition of any of claims 35-37 , wherein the albumin is human serum albumin or albumin from animal species.
39 . The pharmaceutical composition of any of claims 34-38 , wherein the composition further comprises a chemotherapeutic agent.
40 . The pharmaceutical composition of claim 39 , wherein the chemotherapeutic agent is paclitaxel.
41 . A method of treating or preventing a disease or disorder in a subject comprising administering to the subject an effective amount of a composition of any of claims 1-14 , or a compound of any one of claims 15-40 , or a pharmaceutically acceptable salt thereof.
42 . The method of claim 41 , wherein the method further comprises administration of an immunotherapy.
43 . The method of claim 42 , wherein the immunotherapy comprises administration of a PD-1 or PD-L1 antibody.
44 . The method of any of claims 41-43 , wherein the disease or disorder comprises cancer, an autoimmune disease or disorder, or an inflammatory disease or disorder.
45 . The method of any of claims 41-44 , wherein the disease or disorder is cancer.
46 . The method of claim 44 or 45 , wherein the cancer comprises a solid tumor or hematological cancer.
47 . The method of any of claims 44-46 , wherein the cancer is metastatic cancer.
48 . The method of any of claims 44-47 , wherein the disease or disorder is breast cancer, pancreatic cancer, lung cancer, lymphoma.
49 . The method of any of claims 44-48 , wherein the method suppresses or eliminates cancer metastasis, decreases tumor growth, prevents tumor recurrences, or any combination thereof.
50 . The method of any of claims 41-49 , wherein the compound or the composition is administered by subcutaneous injection.
51 . The method of any of claims 42-50 , wherein the immunotherapy is administered at the same time, preceding, or following the compound or the composition.
52 . The method of any of claims 42-51 , wherein the immunotherapy is administered by subcutaneous injection.
53 . The method of any of claims 41-52 , wherein the subject is a human.Join the waitlist — get patent alerts
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